Abstract The molecular mechanisms that control unremitting lung fibrosis remain poorly understood. Progressive fibrosis is a cause of major morbidity and mortality as best exemplified with idiopathic pulmonary fibrosis (IPF). This program has focused on elucidating the roles of the extracellular matrix and matrix receptors in regulating lung inflammation and fibrosis in the context of non-infectious lung injury. Work from our laboratory on this grant over nearly two decades has focused on the role of the extracellular glycosaminoglycan hyaluronan (HA) and HA binding proteins in regulating lung inflammation and fibrosis. We have identified distinct functions for HA depending on both the cellular context of its expression and the form in which it is presented to interacting cells. We have discovered that HA expressed on the cell surface of lung epithelial cells serves a protective function against non-infectious insults. In contrast, when myofibroblasts are directed to over-express hyaluronan synthase 2 (HAS2), the result is a severe and progressive fibrodestructive lung disease that recapitulates key aspects of human disease. One of the pathologic hallmarks of IPF is the destruction of basement membrane and we began to investigate whether fibroblast invasion of matrix could be an important feature of unremitting fibrosis. We have identified invasive fibroblasts in mouse and human and the invasive phenotype requires HAS2 and CD44. We have also discovered a unique pattern of gene expression by matrix-invading fibroblasts that emerge only in the context of matrix interactions. We have begun to lineage-trace the source of fibroblasts and identified that T box gene 4 (Tbx4)-lineage mesenchymal progenitors are the predominant source of myofibroblasts in injured adult murine lung. Furthermore, Tbx4 enabled fibroblast invasion of matrix by regulating HAS2 in both murine models and fibroblasts from patients with IPF. In addition, we discovered that deficiency in HAS2 expression resulted in fibroblast senescence. Despite our progress over the 19-year period of this application, fundamental components of matrix regulation of progressive fibrosis remain unknown. Based on data from novel mouse models and IPF samples, we have generated the hypothesis that expression of HAS2 and HA binding proteins directs fibrogenic processes including fibroblast invasion, myofibroblast differentiation, and fibrosis resolution, resulting in severe and progressive lung fibrosis. These studies will fine tune our understanding of HAS2 and CD44 is distinct mesenchymal populations and the discovery approach has great potential to uncover new therapeutic targets for pulmonary fibrosis. Targeting fibroblast invasion opens up new avenues to therapeutic development for tissue fibrosis.